In recent years, hormone replacement therapy is becoming established as an important method for preventing or treating diseases such as menopausal syndrome (e.g., headaches, hot flushes, sweating, etc.) which often occurs in climacteric or menopausal women, osteoporosis, Alzheimer's disease, arteriosclerosis, and hyperlipemia or for improving the QOL of middle-aged and older women.
In order to prevent, treat, or improve such diseases, a hormone drug is orally administered or injected in most cases. However, it is known that in the case where a female hormone such as a follicular hormone estrogen or a progestational hormone norethisterone is orally administered, the female hormone is absorbed from the alimentary canal and is then rapidly metabolized in the liver. Likewise, it is known that such a female hormone administered by injection is also rapidly metabolized in the liver. Therefore, in either case, the rate of utilization of the drug is significantly low.
Further, there is a possibility that not only impaired liver function but also side effects such as gallbladder disorder and uterine cancer are produced due to a high metabolic rate in the liver. Therefore, it is necessary to keep the drug concentration (i.e., a hormone administered) in the body at a minimum. For this reason, methods for administering a female hormone without allowing the female hormone to pass through the alimentary canal or the liver are being investigated. Among such methods, attention is particularly being given to transdermal absorption preparations from the viewpoint of excellent sustainability in drug release and handleability, and some preparations have already been studied.
For example, Japanese Patent Publication No. Hei 6-51623 discloses a reservoir-type transdermal absorption preparation in which estradiol and norethisterone acetate are dissolved in a gel made of hydroxypropyl cellulose and ethanol. This reservoir-type transdermal absorption preparation controls the release of estradiol and norethisterone acetate by the use of an ethylene-vinyl acetate film. Further, Japanese Patent Laid-Open Publication No. Sho 60-152413 discloses, for example, a transdermal absorption preparation of conjugated estrogens. This transdermal absorption preparation contains menthol as a transdermal absorption promoting agent. However, since these preparations contain a volatile ingredient, there is a fear that drug release characteristics may be changed. In addition, the preparation disclosed in Japanese Patent Publication No. Hei 6-51623 involves the risk of causing skin troubles such as rubor because ethanol contained therein is an irritant to the skin.
Further, International Publication No. WO 91/17752, Japanese Patent Laid-Open Publication No. Hei 5-148145, and Japanese Patent Laid-Open Publication No. 2000-119195 disclose patches manufactured using rubber pressure-sensitive adhesives such as a styrene-isoprene-styrene block copolymer. Furthermore, Japanese Patent Laid-Open Publication No. Sho 61-155321 discloses a patch including, as a main ingredient, an adhesive base material containing an adhesive resin material (e.g., polyterpene resin, hydrocarbon resins), natural rubber or synthetic rubber (e.g., polyisobutylene, styrene-butylene polymer, styrene-isoprene polymer, styrene-ethylene-butylene polymer, 1,4-polyisoprene) and a polymer capable of swelling in water, such as galactomannan. However, since these patches are manufactured using natural rubber or synthetic rubber as a pressure-sensitive adhesive, they are not suitable for prolonged skin application from the viewpoint of the characteristics of natural rubber or synthetic rubber.
In order to solve such a problem, preparations manufactured using acrylic pressure-sensitive adhesives enabling prolonged application are being investigated. As for estradiol, for example, Japanese Patent Laid-Open Publication No. Hei 3-44327, Translated National Publication of Patent Application No. Hei 7-501335, Translated National Publication of Patent Application No. Hei 9-503217, and Translated National Publication of Patent Application No. Hei 9-505554 disclose preparations manufactured using acrylic pressure-sensitive adhesives. Each of the preparations contains its own solvent and absorption accelerator agent to improve the transdermal absorbability of estradiol. However, these preparations are still not perform sufficient transdermal absorption for practical use, because they do not perform enough drug release depending on a solvent and an absorption accelerator agent or some of them are irritants to the skin and they have the risk of causing skin troubles such as rubor as a result of prolonged application.
It is generally difficult to allow an effective amount of drug to permeate through the skin because the skin tissue of a living body basically has a defense function to prevent the entrance of foreign substances into the living body. In order to solve such a problem, an absorption accelerator agent may be added. However, addition of an absorption promoting agent tends to increase the degree of skin irritation in most cases.
As for norethisterone, for example, Japanese Patent Laid-Open Publication No. Hei 4-342532 discloses a patch manufactured using an acrylic pressure-sensitive adhesive comprising 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone. However, since this preparation contains N-vinyl-2-pyrrolidone in a high concentration, norethisterone as a basis is dissolved in the pressure-sensitive adhesive, thus resulting in poor releasability of norethisterone from the preparation. In addition, this preparation has a problem in that it causes strong physical irritation to the skin due to its excessive adhesive strength. Therefore, the preparation cannot be used for prolonged and continuous administration.
Moreover, in the case where an external preparation is administered in hormone replacement therapy, it is necessary to apply the external preparation for a long period of time to maintain an effective blood level of a drug. In order to apply the external preparation for a long period of time, it is necessary to improve the adhesive strength of a base material of the external preparation. In addition, it is particularly necessary to enhance the anchor effect of a pressure-sensitive adhesive on the irregularities of the skin surface in order to increase a holding power. The anchor effect of a pressure-sensitive adhesive on the irregularities of the skin surface can be enhanced by increasing the activity of a polymer compound as an adhesive base material. However, by doing so, there is a possibility that the cohesive strength of the polymer compound is lowered so that cohesion failure occurs, thus resulting in the remaining of the pressure-sensitive adhesive on the skin after peeling-off of the external preparation. Therefore, it is necessary to control the anchor effect of the pressure-sensitive adhesive and the cohesive strength of the pressure-sensitive adhesive to allow the external preparation'to be applied for a long period of time.
In many articles, it has already become apparent that the flexibility of a backing of an external patch has a strong bearing on an increase of the transdermal drug absorption. Examples of a backing having physical properties adequate for this purpose include low-density polymer films, non-woven fabrics, and woven fabrics. It is necessary for them to have a free volume sufficient to obtain flexibility. However, when the free volume of the backing is too large, there is a problem in that drug releasability is lowered after the external patch is stored for a long period of time due to the adsorption of a drug to the backing layer, so that such an external patch cannot deliver satisfactory performance.